or adverse drug reactions in patients with

chronic kidney disease. Table 2 includesresources for more information about dosing adjustments in patients with chronickidney disease.Estimating GFR and Creatinine ClearanceDosages of drugs cleared renally are based onrenal function (calculated as GFR or creatinine clearance; Table 3). These calculationsare valid only when renal function is stableand the serum creatinine level is constant.The K/DOQI clinical practice guidelineadvocates using the traditional CockcroftGault equation or the Modification of Dietin Renal Disease (MDRD) study equation(full or abbreviated) for routine estimationof GFR.1 However, in patients with a GFRlower than 60 mL per minute per 1.73 m 2,the MDRD equation has been shown to besuperior to the Cockcroft-Gault equation.2Because the production and excretion ofcreatinine declines with age, normal serumcreatinine values may not represent normalrenal function in older patients. The MDRDequation has been shown to be the bestmethod for detecting a GFR lower than 90 mLper minute per 1.73 m2 in older patients.3

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Kidney Disease: Dosing

SORT: KEY RECOMMENDATIONS FOR PRACTICEEvidencerating

Clinical recommendation

References

In patients with chronic kidney disease, over-the-counter and herbal medicine use should be assessed to ensurethat medications are indicated; medications with toxic metabolites should be avoided, the least nephrotoxicagents should be used, and alternative medications should be used if potential drug interactions exist.

17, 21, 25,

30, 36, 43

Physicians should be aware of drugs with active metabolites that can exaggerate pharmacologic effects inpatients with renal impairment.

25

Dosages of drugs cleared renally should be adjusted based on the patients renal function (calculated ascreatinine clearance or glomerular filtration rate); initial dosages should be determined using publishedguidelines and adjusted based on patient response; serum drug concentrations should be used tomonitor effectiveness and toxicity when appropriate.

Dosing AdjustmentsLoading doses usually do not need to beadjusted in patients with chronic kidney disease. Published guidelines suggest methodsfor maintenance dosing adjustments: dosereduction, lengthening the dosing interval,or both.4 Dose reduction involves reducingeach dose while maintaining the normaldosing interval. This approach maintainsmore constant drug concentrations, but it isassociated with a higher risk of toxicities ifthe dosing interval is inadequate to allow fordrug elimination. Normal doses are maintained with the extended interval method,but the dosing interval is lengthened to allowtime for drug elimination before redosing.Lengthening the dosing interval has beenassociated with a lower risk of toxicitiesbut a higher risk of subtherapeutic drugTable 1. National Kidney Foundation K/DOQI StagingSystem for Chronic Kidney DiseaseThe rights holder did not grant the American Academy of Family Physiciansthe right to sublicense this material to a third party. For the missing item, seethe original print version of this publication.

1488 American Family Physician

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concentrations, especially toward the end of

the dosing interval.Dosing recommendations for individualdrugs can be found in Drug Prescribing inRenal Failure: Dosing Guidelines for Adults.4The guidelines are divided into three broadGFR categories (less than 10 mL per minuteper 1.73 m2, 10 to 50 mL per minute per1.73 m2, and more than 50 mL per minuteper 1.73 m2), encompassing an up to 10-foldrange in renal function. The guidelines donot correspond with the K/DOQI staging system; therefore, although they canbe used for initial dosages, regimens mustbe individualized further based on patientresponse and serum drug concentrations.antihypertensives

Drug dosing requirements for antihypertensives in patients with chronic kidney diseaseare listed in Table 4.4,5 Thiazide diureticsare first-line agents for treating uncomplicated hypertension,6 but they are not recommended if the serum creatinine level is higherthan 2.5 mg per dL (220 mol per L) or ifthe creatinine clearance is lower than 30 mLper minute.7,8 Loop diuretics are most commonly used to treat uncomplicated hypertension in patients with chronic kidney disease.6Although the addition of aldosterone blockers(e.g., spironolactone [Aldactone], eplerenone[Inspra]) has been shown to reduce mortality in patients with severe heart failure,9,10potassium-sparing diuretics and aldosteroneblockers should be avoided in patients withsevere chronic kidney disease because of therise in serum potassium that typically accompanies renal dysfunction.11-13Volume 75, Number 10

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Kidney Disease: Dosing

Angiotensin-converting enzyme (ACE)

inhibitors and angiotensin receptor blockers(ARBs) are first-line hypertensive agents forpatients with type 1 or 2 diabetes mellitusand proteinuria or early chronic kidneydisease.6 These agents reduce blood pressure and proteinuria, slow the progressionof kidney disease, and provide long-termcardiovascular protection.ACE inhibitors and ARBs inhibit therenin-angiotensin-aldosterone system inpatients with chronic kidney disease and inpatients with normal baseline serum creatinine levels, causing efferent arteriolar dilation. This can cause an acute decline in GFRof more than 15 percent from baseline withproportional elevations in serum creatininewithin the first week of initiating therapy.14-16This most commonly occurs in patientswith congestive heart failure, in patientsusing concomitant diuretics or nonsteroidal anti-inflammatory drugs (NSAIDs), andin patients receiving high doses of ACEinhibitors or ARBs. In most patients, ACEinhibitors and ARBs can be continued safelyif the rise in serum creatinine is less than30 percent. Typically, the level will return tobaseline in four to six weeks.A common practice is to discontinue ACEinhibitor and ARB therapy when the serumcreatinine level rises more than 30 percent orif the serum potassium level is 5.6 mEq per L(5.6 mmol per L) or higher.14-16 Because oflong-term renoprotective and cardioprotective effects, no patient should be denied anACE-inhibitor or ARB trial without carefulevaluation. Dosages should be titrated carefully and followed by weekly monitoring ofrenal function and potassium levels untilvalues return to baseline.Hydrophilic beta blockers (e.g., atenolol[Tenormin], bisoprolol [Zebeta], nadolol[Corgard], acebutolol [Sectral]) are eliminatedrenally and dosing adjustments are needed inpatients with chronic kidney failure.7 However,metoprolol tartrate (Lopressor), metoprololsuccinate (Toprol XL), propranolol (Inderal),and labetalol (Normodyne) are metabolizedby the liver and adjustments are not required.Other antihypertensive agents that do notrequire dosing adjustments include calciumMay 15, 2007

50 to 100 twice daily

*Table provides general dosing information; dosages may be different for specific indications.May need to use lower initial doses in patients receiving diuretics.Less likely than other ACE inhibitors to accumulate in patients with renal failure. A fixed-dose combination with hydrochlorothiazide should notbe used in patients with a creatinine clearance less than 30 mL per minute (0.5 mL per second).Maximal dosage in patients with renal impairment is 10 mg daily.||Thiazides should not be used in patients with a creatinine clearance less than 30 mL per minute; however, thiazides are effective in these patientswhen used with loop diuretics.Information from references 4 and 5.

higher than 1.5 mg per dL (130 mol per L)

in men or higher than 1.4 mg per dL(120 mol per L) in women, in patients olderthan 80 years, or in patients with chronicheart failure.19 The primary concern aboutthe use of metformin in patients with renalinsufficiency is that other hypoxemic conditions (e.g., acute myocardial infarction,severe infection, respiratory disease, liverdisease) increase the risk of lactic acidosis.Physicians may be apprehensive to maximizethe use of metformin in appropriate patientsbecause of these contraindications.A Cochrane review showed that lacticacidosis did not occur in the more than20,000 patients with type 2 diabetes studied(patients with standard contraindications1490 American Family Physician

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to metformin were not included).20 Rather

than avoid the drug completely in patientswith chronic kidney disease, it would bereasonable to start with a low dose in thesepatients and titrate, with close monitoring,based on patient response and tolerability.A more common practice is to temporarilydiscontinue metformin therapy in patientsat a higher risk of lactic acidosis, such aspatients who become septic.Sulfonylureas (e.g., chlorpropamide[Diabinese], glyburide [Micronase]) shouldbe avoided in patients with stages 3 to5 chronic kidney disease.18 The half-life ofchlorpropamide is significantly increasedin these patients, which can cause severehypoglycemia.18 Glyburide has an activeVolume 75, Number 10

Kidney Disease: Dosing

Lack of data in patients with a serum creatinine level higher than 2 mg per dL (180 molper L); therefore, acarbose should be avoided in these patients18

Chlorpropamide(Diabinese)

100 to 500 mg daily

Avoid in patients with a glomerular filtration rate less than 50 mL per minute because ofthe increased risk of hypoglycemia19

Glipizide(Glucotrol)

5 mg daily

Dosage adjustment not necessary in patients with renal impairment

Glyburide(Micronase)

2.5 to 5 mg daily

50 percent of the active metabolite is excreted via the kidney, creating a potential forsevere hypoglycemia; not recommended when creatinine clearance is less than 50 mLper minute (0.83 mL per second)18

Metformin(Glucophage)

500 mg twice daily

Metformin(extendedrelease)

500 mg daily

Avoid if serum creatinine level is higher than 1.5 mg per dL (130 mol per L) in men orhigher than 1.4 mg per dL (120 mol per L) in women, and in patients older than 80years or with chronic heart failure; fixed-dose combination with metformin should beused carefully in renal impairment; metformin should be temporarily discontinued for24 to 48 hours before use of iodinated contrast agents, not restarted for 48 hoursafterward, and then restarted only when renal function has normalized19

*Table provides general dosing information; dosages may be different for specific indications.Information from references 4, 18, and 19.

metabolite that is eliminated renally, and

accumulation of this metabolite can causeprolonged hypoglycemia in patients withchronic kidney disease.18 Glipizide, however,does not have an active metabolite and issafe in these patients.18antimicrobials

Many antimicrobial agents (Table 6 4,21) are

eliminated renally and require dosing adjustments in patients with chronic kidney disease; however, several commonly used agentsdo not require adjustments.21Excessive serum levels of injectable penicillin G or carbenicillin (not available inthe United States) may be associated withneuromuscular toxicity, myoclonus, seizures, or coma.22 Imipenem/cilastatin (Primaxin) can accumulate in patients withchronic kidney disease, causing seizuresif doses are not reduced.23 Patients withadvanced disease should receive a differentcarbapenem, such as meropenem (Merrem).24 Tetracyclines, with the exception ofdoxycycline (Vibramycin), have an antianabolic effect that may significantly worsenthe uremic state in patients with severedisease. Nitrofurantoin (Furadantin) hasa toxic metabolite that can accumulate inpatients with chronic kidney disease, causing peripheral neuritis.25Aminoglycosides should be avoided inpatients with chronic kidney disease whenMay 15, 2007

Volume 75, Number 10

possible. If used, initial doses should be based

on an accurate GFR estimate. Renal functionand drug concentrations should be monitored and dosages adjusted accordingly.analgesics

Patients with stage 5 kidney disease are more

likely to experience adverse effects from opioid use. Metabolites of meperidine (Demerol), dextropropoxyphene (propoxyphene[Darvon]), morphine (Duramorph), tramadol (Ultram), and codeine can accumulate in patients with chronic kidney disease,causing central nervous system and respiratory adverse effects.26-28 These agents are notrecommended in patients with stage 4 or5 disease. A 50 to 75 percent dose reductionfor morphine and codeine is recommendedin patients with a creatinine clearance lessthan 50 mL per minute (0.83 mL per second).28 Extended-release tramadol shouldbe avoided in patients with chronic kidneydisease. The dosing interval of tramadol(regular release) may need to be increased toevery 12 hours in patients with a creatinineclearance less than 30 mL per minute (0.5 mLper second).29 Acetaminophen can be usedsafely in patients with renal impairment.nsaids

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Kidney Disease: Dosing

The rights holder did not grant the American Academy of Family Physicians the right to sublicense thismaterial to a third party. For the missing item, see the original print version of this publication.

Recommended starting dosage is 5 mg daily in persons with a

GFR = glomerular filtration rate.

*Table provides general dosing information; dosages may be different for specific indications.Information from references 37 and 38.

Table 8. Other Common Agents: Dosing Requirements in Patients with Chronic Kidney DiseaseDosage adjustments based on (percentage of usual dosage )GFR (mL per minute per 1.73 m2)Drug

Usual dosage*

> 50

10 to 50

< 10

Allopurinol (Zyloprim)

300 mg daily

75%

50%

25%

Esomeprazole (Nexium)

No adjustment needed

Famotidine (Pepcid)

20 to 40 mg at bedtime

50%

25%

10%

Gabapentin (Neurontin) 39

300 to 600 mg three times daily

900 to 3,600 mgthree times daily(GFR 60)

400 to 1,400 mg twice

daily (GFR > 30 to 59)200 to 700 mg daily(GFR > 15 to 29)

100 to 300 mgdaily(GFR 15)

Lansoprazole (Prevacid)

No adjustment needed

Metoclopramide (Reglan)

10 to 15 mg three times daily

100%

75%

50%

Omeprazole (Prilosec)

No adjustment needed

Ranitidine (Zantac)

150 to 300 mg at bedtime

75%

50%

25%

GFR = glomerular filtration rate.

*Table provides general dosing information; dosages may be different for specific indications.Elimination half-life of active metabolite oxypurinol increases from 24 hours to 125 hours in patients with renal failure. Accumulation of oxypurinol can lead to a toxic immune mediated reaction.Information from references 4 and 39.

failure with or without glomerulopathy, interstitial nephritis, and papillary necrosis.30 Therisk of acute renal failure is three times higherin NSAID users than in non-NSAID users.31Other adverse effects of NSAIDs includedecreased potassium excretion, which cancause hyperkalemia, and decreased sodium1494 American Family Physician

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Kidney Disease: Dosing

adverse gastrointestinal effects, adverse renal

effects are similar to traditional NSAIDs.34,35Short-term use of NSAIDs is generally safein patients who are well hydrated; who havegood renal function; and who do not haveheart failure, diabetes, or hypertension.36Long-term use and high daily dosages ofCOX-2 inhibitors and other NSAIDs shouldbe avoided if possible. Patients at high riskof NSAID-induced kidney disease shouldreceive serum creatinine measurements everytwo to four weeks for several weeks after initiation of therapy because renal insufficiencymay occur early in the course of therapy.

1. National Kidney Foundation. K/DOQI clinical practice

Drug dosing requirements for statins and

for other commonly prescribed medicationsthat require dosing adjustments in patientswith chronic kidney disease are listed inTable 737,38 and Table 8,4,39 respectively.Although herbal therapies are commonlyused,40 some may pose a risk in patients withchronic kidney disease. St. Johns wort andginkgo accelerate the metabolism of manymedications, causing diminished pharmacologic effects. Ginkgo also can increase therisk of bleeding in patients taking aspirin,ibuprofen, or warfarin (Coumadin). Someherbal products (e.g., alfalfa, dandelion,noni juice) contain undisclosed amountsof potassium, which can cause hyperkalemia. Some may contain heavy metals thatare toxic to the kidneys, or ephedra-likevasoconstrictive compounds that can causehypertension.41-43 Chinese herbal medicinescontaining aristolochic acid (commonlyused in weight-loss regimens) are nephrotoxic and can cause stage 5 kidney disease.3This is one in a series of Clinical Pharmacology articlescoordinated by Allen F. Shaughnessy, PharmD, TuftsUniversity Family Medicine Residency Program, Malden,Mass.

The AuthorsMYRNA Y. MUNAR, PharmD, BCPS, is an associateprofessor in the Department of Pharmacy Practice atOregon State University College of Pharmacy, Portland,and is an adjunct assistant professor in the Departmentof Physiology and Pharmacology at the Oregon Healthand Science University School of Medicine, Portland. Dr.Munar received her doctorate of pharmacy degree at the

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Volume 75, Number 10

HARLEEN SINGH, PharmD, is a clinical assistant professor

in the Department of Pharmacy Practice at Oregon StateUniversity College of Pharmacy. Dr. Singh received herdoctorate of pharmacy degree and completed an adultmedicine residency at the Ohio State University College ofPharmacy, Columbus.Address correspondence to Myrna Y. Munar, PharmD,BCPS, 3303 SW Bond Ave., Mail Code CH12C, Portland,OR 97239 (e-mail: munarm@ohsu.edu). Reprints are notavailable from the authors.Author disclosure: Nothing to disclose.REFERENCES